Project 0001 of the Emory University Silvio O. Conte Center for the Neuroscience of Mental Disorders (CCNMD) represents an integral component of the overall Center. We have proposed four studies that in concept or data generated are interrelated to one another and to other basic and clinical projects in this Center proposal. The primary focus is on early life stress induced alterations in neurocircuits and their function. Briefly, the first study (Investigator: Paul M. Plotsky, PhD) extends our knowledge of sensitive periods in development and the sequence of neurocircuits that change in response to an unstable early environment using variations on the rat neonatal maternal separation paradigm. The studies will use behavioral, neuroendocrine (HPA axis function) and CNS gene expression as endpoints. We seek to clarify the relationship between behavioral alterations, HPA axis changes, and adaptations of other central circuits. The second study (Investigators: Kerry Ressler, MD, PhD, & Paul M. Plotsky, PhD) will directly address the role of early life stress induced up-regulation of extra-hypothalamic CRF systems and the locus coeruleus NE system using targeted retrovirus-mediated gene transfer of the rat CRF or tyrosine hydroxylase (TH) genes during different neonatal periods or in adulthood. The third study (Investigators: Donald Rainnie, Ph.DI, & Paul M. Plotsky, PhD)will address important functional issues by assessing how early life stress may alter the balance of signaling in the bed nucleus of the stria terminalis (BNST) such that stress-induced 5-HT input to this region shows a reversal from a stimulatory to inhibitory pattern resulting in a potentially maladaptive response to subsequent stressors. The fourth study (Investigators: M. Mar Sanchez, PhD, & Paul M. Plotsky, PhD) will begin postmortem analyses of gene expression and receptor binding in a sampling of rhesus monkey brains from our existing cohorts (see Conte Monkey Core 9003). Together, these components provide a multifaceted investigation of the long-term consequences of early life stress on neurocircuits in the rat and rhesus models. These data will be important for comparison and interpretation of imaging data obtained in the human studies. Furthermore, they may hold important theoretical implications and clinical relevance. The convergence of excellent animal models, sophisticated scientific questions, cutting edge techniques, and extraordinary expertise among the participants of this project and the Conte Center permit us to address the question of how early life stress affects selected neurocircuits and subsequent behavioral and neuroendocrine in a systematic way.